Thursday, September 13, 2018

There’s a curious incident that took place at the excellent "Schrödinger at 75: The Future of Life" meeting in Dublin last week that I’ve been pondering ever since.

One of the eminent attendees was James Watson, who was, naturally, present at the conference dinner. And one of the movers behind the meeting gave an impromptu (so it seemed) speech that acknowledged Watson’s work with Crick and its connection to Schrödinger’s “aperiodic crystal.” Fair enough.

Then he added that he wanted to recognize also the contribution of the “third man” of DNA, Maurice Wilkins – and who could cavil at that, given Wilkins’ Dublin roots? Wilkins, after all, was another physicist-turned-biologist who credited Schrödinger’s book What Is Life? as an important influence.

I imagined at this stage we might get a nod to the “fourth person” of DNA Rosalind Franklin, whose role was also central but was of course for some years under-recognized. But no. Instead the speaker spoke of how it was when Wilkins showed Watson his X-ray photo of DNA that Watson became convinced crystallography could crack the structure.

You could hear a ripple go around the dining hall. Wilkins’ photo?! Wasn’t it Franklin’s photo – Photo 51 – that provided Watson and Crick with the crucial part of the puzzle?

Well, yes and no. It doesn’t seem too clear who actually took Photo 51, and it seems more likely to have been Franklin’s student Ray Gosling. Neither is it completely clear that this photo was quite so pivotal to Watson and Crick’s success. Neither, indeed, is it really the case that Wilkins did something terribly unethical in showing Watson the photo (which was in any event from the Franklin-Gosling effort), given that it had already been publicly displayed previously. Matthew Cobb examines this part of the story carefully and thoroughly in his book Life’s Greatest Secret (see also here and here).

But nevertheless. Watson’s appalling treatment of Franklin, the controversy about Photo 51, and the sad fact that Franklin died before a Nobel became a possibility, are all so well known that it seemed bizarre, to the point of confrontational, to make no mention of Franklin at all in this context, and right in front of Watson himself to boot.

I figured that the attribution of “the photo” to Wilkins was so peculiar that it could only have another explanation than error or denial. I don’t know the details of the story well enough, but I told myself that the speaker must be referring to some other, earlier occasion when Wilkins had shown Watson more preliminary crystallographic work of his own that persuaded Watson this was an avenue worth pursuing.

And perhaps that is true – I simply don’t know. But if so, to refer to it in this way, when everyone is going to think of the notorious Photo 51 incident, is at best perverse and at worst a deliberate provocation. Even Adam Rutherford, sitting next to me, who knows much more about the story of DNA than I or most other people do, was confused by what he could possibly have meant.

Well, with Franklin’s name still conspicuous by its absence, Watson stood up to take a bow, which prompts me to make a request of scientific meeting and dinner organizers. Please do your attendees the favour of not forcing them to have to decide whether to reluctantly applaud Watson or join the embarrassed cohort of those who feel they can no longer do so in good conscience.

Friday, September 07, 2018

The conference “Schrödinger at 75: The Future of Life” in Dublin, from which I’m now returning, was a fabulous event, packed with good talks equally from eminent folks (including several Nobel laureates) and young rising stars. Ostensibly an exploration of the legacy of Erwin Schrödinger’s influential 1944 book What Is Life?, based on the lectures he gave 75 years ago as director of physical sciences at the Dublin Institute for Advanced Study (on which, more here), it was in fact largely a wonderful excuse to get a bunch of very smart people in the same hall to talk about many areas of the life (and chemical) sciences today and to speculate about what the future holds for them. I think I took away something interesting from every talk.

There was of course much dutiful nodding towards Schrödinger’s book, and also to some of his writing elsewhere, especially his essays in Mind and Matter (1958), where he offered some speculations about mind and consciousness (about half of the speakers worked on aspects of brain, mind and cognition). This didn’t seem merely tokenistic to me – I felt that all the speakers who mentioned Schrödinger had a genuine respect for his ideas. This is all the more interesting given that, as I say in my Nature piece, there wasn’t in some ways a great deal that was truly new and productive of further research in the book. Of course, what gets mentioned most is Schrödinger’s reference to a “code-script” that governs life and which is inherited, and his suggestion that this is encoded in the chromosomes as an “aperiodic crystal”. That image certainly resonated with Francis Crick, who wrote to Schrödinger in 1953 to tell him so.

But the idea of a “code”, as well as the notion that it could be replicated in a manner reminiscent of the ‘templating’ of structure in a crystal, were not really new. It seems rather to be something about the way Schrödinger expressed this idea that mattered, and indeed I can see why: his book is beautifully written, achieving persuasive force without seeming like the imposition of an arrogant physicist.

All of this I enjoyed. But what I missed was a historical presentation that could have put these tributes to What Is Life? in context. There was, for instance, a sense of unease about Schrödinger’s references to “order” and “organization”. What exactly was he getting at here? One suggestion was that “order” here was standing in for that crucial missing word: “information”. But this isn’t really true. Schrödinger’s “code-script” was presented as the means by which an organism’s “organization” is maintained, although quite how it does so he found wholly mysterious, even if the inter-generational transmission of the script by the “aperiodic crystal” was far less so.

What we need to know here is that “organization” had become a biological power-word, a symbol of what it was about living systems that distinguishes them from non-living. In the early nineteenth century this unique property of life was conferred by élan vital in the formulation of vitalism. As vitalism waned, it had to become something more tangible and physical. Some believed, like Thomas Henry Huxley, that the key was a special chemical composition, which made up the stuff of “protoplasm”, the primal living substance from which all life was descended. But as the chemical complexity and heterogeneity of living matter became apparent from the work of late nineteenth-century physiologists, and as the cell came to be seen as the fundamental unit of life, the idea arose that life was distinguished by some peculiar state of “organization” below the level that microscopes could resolve. There were a few tantalizing glimpses of this subcellular organization, for example in the stained chromosome fibres and organelles like the nucleus and mitochondria. These were, however, nothing but blurry blobs, offering no real clue about how their (presumably) molecular nature gave them the apparent agency that distinguished life.

And so, as Andrew Reynolds has shown, “order” and “organization” served a role that was barely more than metaphorical, patching over an ignorance about “what is life”. There’s nothing deplorable about that; it’s the kind of thing science must do all the time, giving a name to an absence of understanding so that it can be contained and built into contingent theories. But for Schrödinger to still be using it in the 1940s shows how his biological reading was rather archaic, for by that stage it had already become apparent that cell physiology relies on enzyme action, and crystallographers like J. Desmond Bernal and Bill Astbury were beginning to apply X-ray crystallography to these proteins to understand their structure. Sure, the origins and nature of the “organization” that cells seemed to exhibit were still pretty obscure, but it was getting less necessary to invoke that nebulous concept.

There were also suggestions at the Dublin meeting that Schrödinger’s “order” was what he meant with his talk of “negative entropy”. There’s some justification to think that, but Schrödinger wasn’t just thinking about how cells prevent their “organization” from falling into entropic disarray. He was puzzled by how this organization could exist in the first place. I don’t think one can really understand his discussion of order and entropy in What Is Life? unless one recognizes that many physical scientists in the early twentieth century considered the molecular world to be fundamentally random. It seems remarkable to me that no accounts of What Is Life? that I have seen refer to Schrodinger’s 1944 essay in Nature on “The Statistical Law in Nature”, where it is almost as if Schrödinger is telling us: ‘this is what I’m thinking about in my book’. The article is a paean to Ludwig Boltzmann, whose influence Schrödinger felt strongly in his early years at Vienna. Schrödinger seems to assert here that there are no laws in nature that do not rely on the statistical averaging over the behaviours of countless microscopic particles. It would have seemed all but meaningless then to suppose that one could speak about law-like, deterministic behaviour at the level of individual molecules, and quantum mechanics had seemed only to confirm this. That is what puzzled Schrödinger so much about the apparent persistence of phenotypic traits that seemed necessarily to arise from the specific details of genes at the molecular scale.

As a consequence, What Is Life? reads a little weirdly to chemists today, or indeed even by the 1950s, to whom the notion that a complex molecule can adopt and sustain a particular structure even in the face of thermal fluctuations seemed unproblematic. Schrödinger’s invocation of quantum mechanics to explain this phenomenon looks rather laboured now, and is quite possibly a part of what irritated Linus Pauling and Max Perutz about the book. It’s also why Schrödinger seems so keen to cement the structure of the gene in place as a “solid”, rather than simply regarding it as a large molecule carrying a linear code.

And what about that code itself? This wasn’t interrogated at the meeting, which was a shame. Indeed, it was sometimes still attributed by speakers the all-mighty agency that Schrödinger himself gave it. It rather astonishes me to see how the claim that the genome contains “all the information you need to make the organism” raises no eyebrows. What surprises me is that scientists are typically a rather sceptical crowd, and demand evidence to support the claims they make. But there is, to my knowledge, no evidence whatsoever that one can make even the simplest organism, let alone a human, from the information contained in the genome. Oh, but surely you can? You can (in principle, and now in some cases in practice) just make the genome from scratch, put it in a cell, and off it goes… Wait. Put it in a cell? So you need a cell to actually enact the “code-script”? Well sure, but the cell goes without saying, right?

Metaphors in biology are always imperfect and often treacherous, but I think this one (a simile, really) has some mileage: saying that the genome is the complete blueprint for an organism is a bit like saying that the Oxford English Dictionary is a blueprint for King Lear. It’s all in there, right? Ok, there’s a lot in there that you don’t need for Lear, but then there’s a lot of junk in the genome too (perhaps!). Sure, to get Lear out of the OED you need to feed the words into William Shakespeare, but Shakespeare goes without saying, right?

For a human, it’s still more complicated. Human cells can of course replicate in a culture medium, but none has ever replicated into an embryo, let alone a person. What they can do – what some induced stem cells can do – is proliferate into an embryoid, an organoid with embryo-like structures. But that won’t make a human. For that, you need not only a cell but a uterus. It’s rather like saying, so the text of King Lear has “all the information” – and then giving it to, say, a Chinese factory worker in Lanzhou. Well OK, so to actually enact Lear in a meaningful way it has to be read by someone who reads English – or translated… But come on, the English goes without saying…

Once we start talking in terms of the information needed to make an organism, though, quite what’s in the genome becomes far less clear. Indeed, we know for sure that maternal factors supply some vital information for the early development of a fertilized egg. And the self-organizing abilities of cells can only create an organism in the right context: every cell needs the right signals from its environment for the whole to assemble properly. Genes somehow encode neurons, but neurons don’t develop properly if they don’t get stimuli from their environment during a critical period.

Are these environmental signals and context then a part of the information needed to make an organism “as nature [meaning evolution, I guess] intends”? Is an understanding of English a part of the information needed for King Lear to be anything more than marks on paper?

Evidently this is an issue of how “information” acquires meaning, which of course was notoriously what Shannon left out of his information theory. And that is why information in Shannon’s sense is greatest when the Shannon entropy is greatest. Periodic solids have rather low entropy. What is needed in biology, then, is a theory for where meaningful information comes from and how it gives rise to causal flows. There’s no doubt that lots of meaningful information is encoded in the genome that contributes to how organisms are built and how they function. But when we say that “the genome contains all the information needed to build an organism”, we are dealing with ill-defined terms. What I solely missed at this meeting was a presentation about how a theory of biological information can be developed, and how to define and measure “meaning” within that theory. Daniel Dennett acknowledged this lacuna in his keynote address, saying that understanding “semantic information” as opposed to Shannon information is still “work in progress”.

A close reading of Schrödinger starts us in that direction too, and is a part of his legacy.